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Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

1
Laboratory of Cell Signaling and Metabolic Disease, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
2
Laboratory for Neural Information Technology, Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan
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Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
5
Nomura Project, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
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Laboratory of Cell Cultures, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
7
Laboratory of Bioinformatics, National Institute of Biomedical Innovation, Saito-Asagi, Ibaraki, Osaka 567-0085, Japan
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Department of Life Science and Biotechnology, Kansai University, Suita, Osaka 564-8680, Japan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2014, 5(4), 1095-1114; https://doi.org/10.3390/genes5041095
Received: 14 October 2014 / Revised: 12 November 2014 / Accepted: 2 December 2014 / Published: 11 December 2014
(This article belongs to the Section Molecular Genetics and Genomics)
Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds. View Full-Text
Keywords: GRID2; GluRδ2; memantine; NMDA receptor; cerebellum GRID2; GluRδ2; memantine; NMDA receptor; cerebellum
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Kumagai, A.; Fujita, A.; Yokoyama, T.; Nonobe, Y.; Hasaba, Y.; Sasaki, T.; Itoh, Y.; Koura, M.; Suzuki, O.; Adachi, S.; Ryo, H.; Kohara, A.; Tripathi, L.P.; Sanosaka, M.; Fukushima, T.; Takahashi, H.; Kitagawa, K.; Nagaoka, Y.; Kawahara, H.; Mizuguchi, K.; Nomura, T.; Matsuda, J.; Tabata, T.; Takemori, H. Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line. Genes 2014, 5, 1095-1114.

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